TY - JOUR
T1 - Zfta–rela dictates oncogenic transcriptional programs to drive aggressive supratentorial ependymoma
AU - Arabzade, Amir
AU - Zhao, Yanhua
AU - Varadharajan, Srinidhi
AU - Chen, Hsiao Chi
AU - Jessa, Selin
AU - Rivas, Bryan
AU - Stuckert, Austin J.
AU - Solis, Minerva
AU - Kardian, Alisha
AU - Tlais, Dana
AU - Golbourn, Brian J.
AU - Stanton, Ann Catherine J.
AU - Chan, Yuen San
AU - Olson, Calla
AU - Karlin, Kristen L.
AU - Kong, Kathleen
AU - Kupp, Robert
AU - Hu, Baoli
AU - Injac, Sarah G.
AU - Ngo, Madeline
AU - Wang, Peter R.
AU - De León, Luz A.
AU - Sahm, Felix
AU - Kawauchi, Daisuke
AU - Pfister, Stefan M.
AU - Lin, Charles Y.
AU - Hodges, H. Courtney
AU - Singh, Irtisha
AU - Westbrook, Thomas F.
AU - Chintagumpala, Murali M.
AU - Blaney, Susan M.
AU - Parsons, Donald W.
AU - Pajtler, Kristian W.
AU - Agnihotri, Sameer
AU - Gilbertson, Richard J.
AU - Yi, Joanna
AU - Jabado, Nada
AU - Kleinman, Claudia L.
AU - Bertrand, Kelsey C.
AU - Deneen, Benjamin
AU - Mack, Stephen C.
N1 - Funding Information:
S.C. Mack is supported by a V Foundation Scholar in Cancer Research Award, Cancer Prevention Research Institute of Texas (CPRIT) scholar award (RR170023), Alex’s Lemonade Stand Foundation (ALSF) A award, THINC Seed Grant, and NIH-National Institute of Neurological Disease and Stroke (R01NS116361). We acknowledge the joint participation of the Adrienne Helis Malvin Medical Research Foundation, and Baylor College of Medicine. K.C. Bertrand is supported by grant funding from Hyundai Hope on Wheels, Rally Foundation, and St. Baldrick’s Foundation Early Career Development Award. J. Yi is supported by a THINC Seed Grant, K12 award (5K12CA090433-17), and an Alex’s Lemonade Stand Foundation Center of Excellence Developmental Therapeutic Scholar Award. C.L. Kleinmann is supported by Canadian Institutes of Health Research (CIHR) #PJT-156086 and NSERC RGPIN-2016-04911. B. Deneen is supported by National Cancer Institute-Cancer Therapeutic Discovery (U01-CA217842) and Cancer Prevention Research Institute of Texas (RP150334). H. Hodges is supported by grants from CPRIT (RR170036), NCI (R00CA187565), and NIGMS (R35GM137996). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
K. Kong reports grants from F32 Postdoctoral Fellowship during the conduct of the study. S.G. Injac reports non-financial support from Takeda Pharmaceuticals outside the submitted work. F. Sahm reports other support from Illumina outside the submitted work. S.M. Pfister reports grants from IMI-2 project together with various companies (Eli Lilly, Roche, Bayer, Pfizer, Pharmamar, AstraZeneca, Johnson and Johnson) outside the submitted work; in addition, S.M. Pfister has a European Patent (16 710 700.2) for DNA-Methylation Based Method for Classifying Tumor Species issued. C.Y. Lin reports other support from Kronos Bio., Inc. outside the submitted work. R.J. Gilbertson reports a patent for PCT/EP2020/063096 issued to Cancer Research Technology Limited & MedImmune Limited. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/9
Y1 - 2021/9
N2 - More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus ) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we devel-oped an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with Plagl family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by Plagl TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.
AB - More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus ) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we devel-oped an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with Plagl family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by Plagl TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.
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U2 - 10.1158/2159-8290.CD-20-1066
DO - 10.1158/2159-8290.CD-20-1066
M3 - Article
C2 - 33741710
AN - SCOPUS:85106672207
VL - 11
SP - 2200
EP - 2215
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 9
ER -